APPLICANT'S ABSTRACT: This application was submitted in response to NIDA RFA DA-96-002, Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP). We propose a series of integrated preclinical and clinical studies designed to identify novel anti-cocaine medications and to evaluate both agonist and antagonist approaches to the treatment of cocaine addiction. Four inter-related research projects (conducted at five independent sites) will focus on medicinal chemistry, preclinical behavioral pharmacology, preclinical cardiovascular physiology and inpatient clinical evaluations. The research program will be managed through an Administrative Core, and a SPIRCAP Steering Committee will guide the overall program direction and ensure communication between the component projects and MDD/NIDA in a cooperative study agreement (U19). We propose to evaluate the safety and efficacy of two classes of novel anti-cocaine medications: (1) full and partial dopamine D1 agonists, and (2) kappa opioid agonists. Full dopamine D1 agonists mimic some behavioral effects of cocaine and will allow an examination of the "substitution-agonist" concept of therapy. Partial dopamine D1 agonists and kappa opioid agonists block some behavioral effects of cocaine and will allow an evaluation of the "antagonist" concept of therapy. Both types of medications will be evaluated in parallel studies conducted under identical conditions. First, the effects of chronic treatment with each medication on i.v. cocaine and food self-administration will be examined in rhesus monkeys. The effect of a range of doses of the treatment medications on cocaine dose-effect curves will be studied. Subsequently, each treatment will be examined in progressive ratio tests of cocaine self-administration to determine medication effects on cocaine's reinforcing efficacy. Since cocaine has potentially lethal cardiovascular and cerebrovascular toxicity, the safety of behaviorally effective treatment medications, alone, and in combination with cocaine, also will be examined in preclinical studies of cardiovascular physiology. The results of these preclinical evaluations of safety and efficacy will determine the sequence of novel medications examined in clinical laboratory studies. Clinical evaluation of novel treatments will require application for an IND to FDA for safety and efficacy studies. We propose to examine single doses of each promising novel treatment medication in inpatient studies under controlled clinical research ward conditions. The physiological, subjective and neuroendocrine effects of each treatment will be evaluated, alone, and in combination with two doses of cocaine, under single-blind conditions. The results of these 5-day inpatient studies will determine the feasibility of conducting 30-day studies to evaluate the effects of chronic administration of each novel treatment. This comprehensive, integrated research program will identify the most safe and effective medication for cocaine treatment and suggest the basic mechanisms of its anti-cocaine actions.